The etiology of Parkinson's disease (PD) is currently unknown and treatment is unable to halt disease progression. Microglias, the innate immune cells of the brain, are implicated in PD progression, but the mechanisms driving continuous and pathologically activated microglia are poorly understood. Environmental factors are associated with PD etiology and can chronically activate microglia to cause dopaminergic (DA) neuron damage. Microglial NADPH oxidase and reactive oxygen species have been strongly been implicated as key elements of toxic microglial activation, but how they regulate microglial function is largely unknown. Our overarching hypothesis is that environmental insult causes chronic neuroinflammation and consequent progressive DA neuron damage through changes in microglial protein radical biochemistry. Thus, beginning with the NF:2 p50 radical, we will test the specific hypothesis that paraquat, LPS, and MPTP/MPP+ cause microglial protein radicals that drive progressive neuroinflammation and DA neurotoxicity by: A) enhancing the production of neurotoxic pro- inflammatory factors (microglial priming);B) mediating the failure of microglia to resolve the pro- inflammatory response. Preliminary data indicate that microglia respond to pro-inflammatory toxins (LPS), direct neurotoxicants (MPTP/MPP+, reactive microgliosis), and dual-mode toxicants (paraquat) by changing their protein radical profile and increasing expression of the cytosolic NF:ss p50 radical. Thus, beginning with the NF:ss p50 radical, the specific aims are to: 1) identify the pro-inflammatory and priming characteristics of microglial protein radicals in vitro (NF:ss p50 radical);2) characterize the role of the NF:ss p50 radical in progressive DA neuron damage in vivo;3) determine the neuroprotective and anti-inflammatory effect of inhibiting NF:ss p50 radical formation. 1We expect to systematically demonstrate for the first time that the NF:ss p50 radical is a common mechanism of environmentally- induced deleterious microglial activation that fuels progressive DA neurotoxicity. These studies will define a new avenue of research in PD pathogenesis, ROS-signaling, and the role of environmentally-induced oxidative stress in neurodegenerative disease. Finally, this work will provide valuable insight into the identification and timing of novel therapeutic targets capable of slowing PD progression. PUBLIC HEALTH RELEVANCE These studies will define a new avenue of research in Parkinson's disease pathogenesis and the role of environmentally-induced oxidative stress in neurodegenerative disease. Finally, this work will provide valuable insight into the identification and timing of novel therapeutic targets capable of slowing Parkinson's disease progression.